This project involves the conduct of a lentivector-mediated IL2RG gene therapy clinical trial using autologous blood stem cell gene therapy to treat X-linked severe combined immune deficiency. X-linked severe combined immunodeficiency (XSCID) is caused by mutations in the IL2RG gene encoding the common gamma chain (gc) of receptors for interleukins (IL)-2, -4, -7, -9, -15 and -21. Our goal is to investigate the safety and efficacy of gene transfer treatment as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant(s). In our now closed earlier protocol that provided background to the current lentivector protocol, we used gamma-retroviral vector to mediate the gene transfer without any conditioning regimen, which did not achieve sustained correction and expansion of the genetically corrected lymphoid cells. We published the first report of the first five of six older subjects with partially corrected X-SCID have in April 2016, treated using a integrating lentivector developed in collaboration with extramural investigators (Dr Brian Sorrentino) at St Jude Children's Research Hospital, Memphis. This gene therapy treatment was given combined with mild/moderate dose of busulfan 6mg/kg total for myelo-conditioning (De Ravin SS, et al. Sci Transl Med April 2016). Following that report, we treated another 3 patients, making a total of 8 patients (Cohort A). While most patients achieved clinical benefits, there was some variability of relatively low vector copy numbers in Cohort A, and availability of clinical vector also presented a challenge. To address these problems, we further optimized transduction procedures which include the use of transduction enhancers that has achieved consistently increased transduction efficiencies despite using significantly less vector. Analysis of the transgene integration continues to show polyclonal integration patterns, without any growing dominance of any particular clones, and we will continue to monitor closely the progression of higher copy-number grafts.